The fatal dose of Oxytocinum syntheticum has not been established. Oxytocinum syntheticum is subject to inactivation by proteolytic enzymes of the alimentary tract. Hence it is not absorbed from the intestine and is not likely to have toxic effects when ingested.
8 Undesirable effects. In addition, as a result of uterine overstimulation, placental abruption and/or amniotic fluid embolism have been reported.Treatment: When signs or symptoms of overdosage occur during continuous IV administration of Oxytocinum syntheticum, the infusion must be discontinued at once and oxygen should be given to the mother. In cases of water intoxication it is essential to restrict fluid intake, promote diuresis, correct electrolyte imbalance, and control convulsions that may eventually occur. In the case of coma, a free airway should be maintained with routine measures normally employed in the nursing of the unconscious patient.
- Hypertonic uterine contractions, mechanical obstruction to delivery, foetal distress.
Any condition in which, for foetal or maternal reasons, spontaneous labour is inadvisable and/or vaginal delivery is contra-indicated: e.g.:
- Significant cephalopelvic disproportion
- Foetal malpresentation
- Placenta praevia and vasa praevia
- Placental abruption
- Cord presentation or prolapse
- Overdistension or impaired resistance of the uterus to rupture as in multiple pregnancy
- Polyhydramnios
- Grand multiparity
- In the presence of a uterine scar resulting from major surgery including classical caesarean section.
Oxytocinum syntheticum should not be used for prolonged periods in patients with Oxytocinum syntheticum-resistant uterine inertia, severe pre-eclamptic toxaemia or severe cardiovascular disorders.
Oxytocinum syntheticum should not be infused via the same apparatus as blood or plasma, because the peptide linkages are rapidly inactivated by Oxytocinum syntheticum-inactivating enzymes. Oxytocinum syntheticum is incompatible with solutions containing sodium metabisulphite as a stabiliser.
As there is a wide variation in uterine sensitivity, uterine spasm may be caused in some instances by what are normally considered to be low doses. When Oxytocinum syntheticum is used by IV infusion for the induction or enhancement of labour, administration at too high doses results in uterine overstimulation which may cause foetal distress, asphyxia, and death, or may lead to hypertonicity, tetanic contractions, soft tissue damage or rupture of the uterus.
These rapid haemodynamic changes may result in myocardial ischaemia, particularly in patients with pre-existing cardiovascular disease. Rapid IV bolus injection of Oxytocinum syntheticum at doses amounting to several IU may also lead to QTc prolongation.Water intoxication
Special warnings and precautions for use).Symptoms of water intoxication include:
1. Headache, anorexia, nausea, vomiting and abdominal pain.
2. Lethargy, drowsiness, unconsciousness and grand-mal type seizures.
3. Low blood electrolyte concentration.
Undesirable effects (Tables 1 and 2) are ranked under heading of frequency, the most frequent first, using the following convention: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports; not known (cannot be estimated from the available data). The ADRs tabulated below are based on clinical trial results as well as postmarketing reports.
The adverse drug reactions derived from post-marketing experience with Oxytocinum syntheticum are via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.
Table 1 Adverse drug reactions in mother
| System organ class | Adverse drug reaction |
| Immune system disorders | Rare: Anaphylactic/Anaphylactoid reaction associated with dyspnoea, hypotension or Anaphylactic/Anaphylactoid Shock |
| Nervous system disorders | Common: Headache |
| Cardiac disorders | Common: Tachycardia, bradycardia Uncommon: Arrhythmia Not known: Myocardial ischaemia, Electrocardiogram QTc prolongation |
| Vascular disorders | Not known: Hypotension, haemorrhage |
| Gastrointestinal disorders | Common: Nausea, vomiting |
| Skin and subcutaneous tissue disorders | Rare: Rash |
| Pregnancy, puerperium and perinatal conditions | Not known: Uterine hypertonus, tetanic contractions of uterus, rupture of the uterus |
| Metabolism and nutrition disorders | Not known: Water intoxication, maternal hyponatraemia |
| Respiratory, thoracic and mediastinal disorders | Not known: acute pulmonary oedema |
| General disorders and administration site conditions | Not known: Flushing |
| Blood and lymphatic system disorders | Not known: disseminated intravascular coagulation |
| Skin and subcutaneous tissue disorders | Not Known: Angioedema |
Table 2 Adverse drug reactions in foetus/neonate
| System organ class | Adverse drug reaction |
| Pregnancy, puerperium and perinatal conditions | Not known: foetal distress, asphyxia and death |
| Metabolism and nutrition disorders | Not known: Neonatal hyponatraemia |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: www.mhra.gov.uk/yellowcard.
Pre-clinical data for Oxytocinum syntheticum reveal no special hazard for humans based on conventional studies of single dose acute toxicity, genotoxicity, and mutagenicity.
Antepartum
- Induction of labour for medical reasons, e.g. in cases of post-term gestation, premature rupture of the membranes, pregnancy-induced hypertension (pre-eclampsia)
- Stimulation of labour in hypotonic uterine inertia
- Early stages of pregnancy as adjunctive therapy for the management of incomplete, inevitable, or missed abortion
Postpartum
- During caesarean section, but following delivery of the child
- Prevention and treatment of postpartum uterine atony and haemorrhage
Pharmacotherapeutic group: Posterior pituitary lobe hormones
ATC code: H01B B02
Mechanism of action
Oxytocinum syntheticum is a cyclic nonapeptide that is obtained by chemical synthesis. This synthetic form is identical to the natural hormone that is stored in the posterior pituitary and released into the systemic circulation in response to suckling and labour.
Oxytocinum syntheticum stimulates the smooth muscle of the uterus, more powerfully towards the end of pregnancy, during labour, and immediately postpartum. At these times, the Oxytocinum syntheticum receptors in the myometrium are increased.
The Oxytocinum syntheticum receptors are G-proteins coupled receptors. Activation of receptor by Oxytocinum syntheticum triggers release of calcium from intracellular stores and thus leads to myometrial contraction.
Oxytocinum syntheticum elicits rhythmic contractions in upper segment of uterus, similar in frequency, force and duration to those observed during labour.
Being synthetic, Oxytocinum syntheticum in Oxytocinum syntheticum does not contain vasopressin, but even in its pure form Oxytocinum syntheticum possesses some weak intrinsic vasopressin-like antidiuretic activity.
Based on in vitro studies, prolonged exposure of Oxytocinum syntheticum had been reported to cause desensitisation of Oxytocinum syntheticum receptors probably due to down-regulation of Oxytocinum syntheticum-binding sites, destabilisation of Oxytocinum syntheticum receptors mRNA and internalisation of Oxytocinum syntheticum receptors.
Plasma levels and onset/duration of effect
Intravenous infusion. When Oxytocinum syntheticum is given by continuous IV infusion at doses appropriate for induction or enhancement of labour, the uterine response sets in gradually and usually reaches a steady state within 20 to 40 minutes. The corresponding plasma levels of Oxytocinum syntheticum are comparable to those measured during spontaneous first-stage labour. For example, Oxytocinum syntheticum plasma levels in 10 pregnant women at term receiving a 4 milliunits per minute intravenous infusion were 2 to 5 microunits/mL. Upon discontinuation of the infusion, or following a substantial reduction in the infusion rate, e.g. in the event of overstimulation, uterine activity declines rapidly but may continue at an adequate lower level.
Absorption
Plasma levels of Oxytocinum syntheticum following intravenous infusion at 4 milliunits per minute in pregnant women at term were 2 to 5 microunits/mL.
Distribution
The steady-state volume of distribution determined in 6 healthy men after IV injection is 12.2 L or 0.17 L/kg. Plasma protein binding is negligible for Oxytocinum syntheticum. It crosses the placenta in both directions. Oxytocinum syntheticum may be found in small quantities in mother's breast milk.
Biotransformation/Metabolism
Oxytocinum syntheticumase is a glycoprotein aminopeptidase that is produced during pregnancy and appears in the plasma. It is capable of degrading Oxytocinum syntheticum. It is produced from both the mother and the foetus. Liver and kidney plays a major role in metabolising and clearing Oxytocinum syntheticum from the plasma. Thus, liver, kidney and systemic circulation contribute to the biotransformation of Oxytocinum syntheticum.
Elimination
Plasma half-life of Oxytocinum syntheticum ranges from 3 to 20 min. The metabolites are excreted in urine whereas less than 1% of the Oxytocinum syntheticum is excreted unchanged in urine. The metabolic clearance rate amounts to 20 mL/kg/ min in the pregnant woman.
Renal impairment
No studies have been performed in renally impaired patients. However, considering the excretion of Oxytocinum syntheticum and its reduced urinary excretion because of anti-diuretic properties, the possible accumulation of Oxytocinum syntheticum can result in prolonged action.
Hepatic impairment
No studies have been performed in hepatically impaired patients. Pharmacokinetic alteration in patients with impaired hepatic function is unlikely since metabolising enzyme, Oxytocinum syntheticumase, is not confined to liver alone and the Oxytocinum syntheticumase levels in placenta during the term has significantly increased. Therefore, biotransformation of Oxytocinum syntheticum in impaired hepatic function may not result in substantial changes in metabolic clearance of Oxytocinum syntheticum.
Oxytocinum syntheticum must only be administered as an IV infusion and never by IV bolus injection as it may cause an acute short-lasting hypotension accompanied with flushing and reflex tachycardia.
Induction of labour
The induction of labour by means of Oxytocinum syntheticum should be attempted only when strictly indicated for medical reasons. Administration should only be under hospital conditions and qualified medical supervision.
Cardiovascular disorders
Oxytocinum syntheticum should be used with caution in patients who have a pre-disposition to myocardial ischaemia due to pre-existing cardiovascular disease (such as hypertrophic cardiomyopathy, valvular heart disease and/or ischaemic heart disease including coronary artery vasospasm), to avoid significant changes in blood pressure and heart rate in these patients.
QT Syndrome
When Oxytocinum syntheticum is given for induction and enhancement of labour:
- Foetal distress and foetal death: Administration of Oxytocinum syntheticum at excessive doses results in uterine overstimulation which may cause foetal distress, asphyxia and death, or may lead to hypertonicity, tetanic contractions or rupture of the uterus.
Careful monitoring of foetal heart rate and uterine motility (frequency, strength, and duration of contractions) is essential, so that the dosage may be adjusted to individual response.
- Particular caution is required in the presence of borderline cephalopelvic disproportion, secondary uterine inertia, mild or moderate degrees of pregnancy-induced hypertension or cardiac disease, and in patients above 35 years of age or with a history of lower-uterine-segment caesarean section.
- Disseminated intravascular coagulation: In rare circumstances, the pharmacological induction of labour using uterotonic agents, including Oxytocinum syntheticum increases the risk of postpartum disseminated intravascular coagulation (DIC). The pharmacological induction itself and not a particular agent is linked to such risk. This risk is increased in particular if the woman has additional risk factors for DIC such as being 35 years of age or over, complications during pregnancy and gestational age more than 40 weeks. In these women, Oxytocinum syntheticum or any other alternative drug should be used with care, and the practitioner should be alerted by signs of DIC.
Intrauterine death
In the case of foetal death in utero, and/or in the presence of meconium-stained amniotic fluid, tumultuous labour must be avoided, as it may cause amniotic fluid embolism.
Water intoxication
Because Oxytocinum syntheticum possesses slight antidiuretic activity, its prolonged IV administration at high doses in conjunction with large volumes of fluid, as may be the case in the treatment of inevitable or missed abortion or in the management of postpartum haemorrhage, may cause water intoxication associated with hyponatraemia. The combined antidiuretic effect of Oxytocinum syntheticum and the IV fluid administration may cause fluid overload leading to a haemodynamic form of acute pulmonary oedema without hyponatraemia. To avoid these rare complications, the following precautions must be observed whenever high doses of Oxytocinum syntheticum are administered over a long time: an electrolyte-containing diluent must be used (not dextrose); the volume of infused fluid should be kept low (by infusing Oxytocinum syntheticum at a higher concentration than recommended for the induction or enhancement of labour at term); fluid intake by mouth must be restricted; a fluid balance chart should be kept, and serum electrolytes should be measured when electrolyte imbalance is suspected.
Renal Impairment
Caution should be exercised in patients with severe renal impairment because of possible water retention and possible accumulation of Oxytocinum syntheticum.
Oxytocinum syntheticum can induce labour, therefore caution should be exercised when driving or operating machines. Women with uterine contractions should not drive or use machines.
Induction or enhancement of labour: Oxytocinum syntheticum should not be started for 6 hours following administration of vaginal prostaglandins.). To ensure even mixing, the bottle or bag must be turned upside down several times before use.
The initial infusion rate should be set at 1 to 4 milliunits/minute (2 to 8 drops/minute). It may be gradually increased at intervals not shorter than 20 minutes and increments of not more than 1-2 milliunits/minute, until a contraction pattern similar to that of normal labour is established. In pregnancy near term this can often be achieved with an infusion of less than 10 milliunits/minute (20 drops/minute), and the recommended maximum rate is 20 milliunits/minute (40 drops/minute). In the unusual event that higher rates are required, as may occur in the management of foetal death in utero or for induction of labour at an earlier stage of pregnancy, when the uterus is less sensitive to Oxytocinum syntheticum, it is advisable to use a more concentrated Oxytocinum syntheticum solution, e.g., 10 IU in 500ml.
When using a motor-driven infusion pump which delivers smaller volumes than those given by drip infusion, the concentration suitable for infusion within the recommended dosage range must be calculated according to the specifications of the pump.
The frequency, strength, and duration of contractions as well as the foetal heart rate must be carefully monitored throughout the infusion. Once an adequate level of uterine activity is attained, aiming for 3 to 4 contractions every 10 minutes, the infusion rate can often be reduced. In the event of uterine hyperactivity and/or foetal distress, the infusion must be discontinued immediately.
If, in women who are at term or near term, regular contractions are not established after the infusion of a total amount of 5 IU, it is recommended that the attempt to induce labour be ceased; it may be repeated on the following day, starting again from a rate of 1 to 4 milliunits/minute.
Incomplete, inevitable, or missed abortion: 5 IU by IV infusion (5 IU diluted in physiological electrolyte solution and administered as an IV drip infusion or, preferably, by means of a variable-speed infusion pump over 5 minutes), if necessary followed by IV infusion at a rate of 20 to 40 milliunits/minute.
Caesarean section: 5 IU by IV infusion (5 IU diluted in physiological electrolyte solution and administered as an IV drip infusion or, preferably, by means of a variable-speed infusion pump over 5 minutes) immediately after delivery.
Prevention of postpartum uterine haemorrhage: The usual dose is 5 IU by IV infusion (5 IU diluted in physiological electrolyte solution and administered as an IV drip infusion or, preferably, by means of a variable-speed infusion pump over 5 minutes) after delivery of the placenta. In women given Oxytocinum syntheticum for induction or enhancement of labour, the infusion should be continued at an increased rate during the third stage of labour and for the next few hours thereafter.
Treatment of postpartum uterine haemorrhage: 5 IU by IV infusion (5 IU diluted in physiological electrolyte solution and administered as an IV drip infusion or, preferably, by means of a variable-speed infusion pump over 5 minutes), followed in severe cases by IV infusion of a solution containing 5 to 20 IU of Oxytocinum syntheticum in 500ml of an electrolyte-containing diluent, run at the rate necessary to control uterine atony.
Route of administration: Intravenous infusion.
Special populations
Renal impairment
No studies have been performed in renally impaired patients.
Hepatic impairment
No studies have been performed in hepatically impaired patients.
Paediatric population
No studies have been performed in paediatric patients.
Elderly population
No studies have been performed in elderly patients (65 years old and over).
Snap ampoules: no file required.
Oxytocinum syntheticum is compatible with the following infusion fluids: sodium chloride 0.9 %, dextrose 5 %, Ringer's solution, acetated Ringer's solution.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
